Project Summary/Abstract The overarching goals of this project are to advance knowledge of the complex pathophysiology of distal symmetric polyneuropathies (DSP) and frame future interventions for nutritional neuropathies in Zambia through: 1) assessment of population-based estimates and risk factors for DSP in Zambia?s maize and cassava staple food zones; 2) comparison of population-based estimates and risk factors to previous clinic- based data from the same maize-staple districts; 3) and assessing the odds of specific micronutrient deficiencies among DSP cases and age, gender, and HIV-matched controls from the same districts. To accomplish these goals, Dr. Kvalsund will focus on acquisition of additional expertise and experience in the following key areas: 1) advanced epidemiological methods and analysis; 2) clinical trials methodologies, 3) global health policy; 4) neuropathy outcome assessments; and 5) HIV and nutrition. The needed skills will be achieved through structured mentorship, coursework, and pragmatic clinical trials and health policy experiences. The research-training plan will provide Dr. Kvalsund with the additional proficiency necessary to undertake future intervention research aimed at reducing nutrition-associated neurologic morbidity in Zambia and advancing scientific knowledge of the pathophysiologic mechanisms that generate DSP as a common phenotype. The central hypothesis is that the high rate of DSP previously observed in clinic populations in Zambia is equally prevalent outside healthcare settings owing to common endemic infectious diseases and their neurotoxic treatments, food insecurity and low dietary diversity, recurrent nutritional challenges, specific micronutrient deficiencies and their interactions, and possibly other unidentified latent factors. We hypothesize that folate-deficiency will be highly associated with DSP in Zambian communities, as has been documented in clinic populations, and may warrant a targeted public health intervention given the preventable nature and range of other neurologic morbidities also associated with folate deficiencies. The specific aims are to: 1) Determine population-based DSP estimates in Zambia; 2) Compare and contrast DSP estimates and risk factors with those from clinical settings in Zambia; 3) to consider the relative contributions of urbanicity, agroecological/staple food zone, and specific micronutrient deficiencies on DSP prevalence; and 4) Evaluate for latent environmental or toxico-dietary factors as contributors to DSP in this environment. The research is expected to provide the foundation for future R-01 intervention and observational research and to improve scientific understanding of how diverse etiologies, multiple exposures and interactions lead to a common clinicopathologic DSP phenotype, which remains poorly understood to date.